Allogeneic Hematopoietic Stem Cell Transplant for People With Primary Immunodeficiency Diseases

  • STATUS
    Recruiting
  • End date
    Nov 30, 2025
  • participants needed
    56
  • sponsor
    National Cancer Institute (NCI)
Updated on 12 September 2021
cancer
stem cell transplantation
total body irradiation
fludarabine
tacrolimus
mycophenolate mofetil
cyclophosphamide
immunodeficiency
busulfan
ejection fraction
bone marrow procedure
vaccination
schwartz
blood transfusion
pulmonary function tests
conjugated bilirubin
alemtuzumab
autoimmune disease
therapeutic agents
cytoxan
allogeneic hematopoietic stem cell transplant
hemophagocytic lymphohistiocytosis
hypogammaglobulinemia
primary immunodeficiency

Summary

Background

During a transplant, blood stem cells from one person are given to someone else. The cells grow into the different cells that make up the immune system. This can cure people with certain immunodeficiencies. But transplant has many risks and complications.

Objective

To see if stem cell transplant can be successfully performed in people with primary immunodeficiency disease and cure them.

Eligibility

People ages 4-69 for whom a primary immunodeficiency (PID) or Primary Immune Regulatory Disorder (PIRD), has caused significant health problems and either standard management has not worked or there are no standard management options, along with their donors

Design

Donors will be screened under protocol 01-C-0129. They will donate blood or bone marrow.

Participants will be screened with:

Medical history

Physical exam

Blood, urine, and heart tests

CT or PET scans

Before transplant, participants will have dental and eye exams. They will have a bone marrow biopsy. For this, a needle will be inserted through the skin into the pelvis to remove marrow.

Participants will be hospitalized before their transplant. They will have a central catheter put into a vein in their chest or neck. They will get medications through the catheter to prevent complications. Participants will get stem cells through the catheter. They will stay in the hospital for at least 4 weeks. They will give blood, urine, bone marrow, and stool samples. They may need blood transfusions. They may need more scans. They will take more medications.

Participants will have visits on days 30, 60, 100, 180, and 360, and 24 months after the transplant. Then they will have visits once a year for about 5 years

Description

Background
  • With the availability of whole exome sequencing (WES) and whole genome sequencing (WGS) for patients with suspected primary immune deficiency or Primary Immune Regulatory Disorder (PIRD), the number of recognized PID s and PIRD s has increased in recent years to over 400 distinct immune defects.
  • Allogeneic hematopoietic stem cell transplantation represents a potentially curative therapy for many hematologic diseases.
  • Hematopoietic stem cell transplant is now an accepted standard or an appropriate experimental approach for treatment of an increasing number of PID
  • The use of conditioning regimens containing high doses of alkylating agents, often in combination with total body irradiation, are considered myeloablative and are essential and for suppression of the host-versus-graft response to the donor stem cells (i.e. rejection)
  • We propose to evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation (HSCT) using selected conditioning regimens and selected donor sources in reconstituting normal hematopoiesis and immune function and reversing the disease phenotype in patients with primary immunodeficiency diseases.
    Objectives

-To determine whether allogeneic HSCT results in sustained donor engraftment defined as neutrophil recovery with ANC greater than or equalto 500/mm(3) for 3 consecutive days associated with > 50% donor T-cell and myeloid cell donor chimerism before day 100 for diseases characterized by loss of function and >75% donor T-cell and myeloid cell chimerism for diseases characterized by gain-of-function mutations.

Eligibility
  • Participants ages 4-69 years old with a known PID or PIRD, or with clinical evidence of a PID or PIRD with a history of recurrent infections requiring prolonged courses of therapy, or evidence of immune dysregulation manifested by autoimmune/autoinflammatory disease, atopy, hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, or impaired response to vaccination. A virally-driven malignancy alone will also constitute a basis for inclusion.
  • Have a 10/10 or a 9/10 or 8/10 HLA-matched related or unrelated donor (HLA -A, -B, -C, DRB1, DQB1 by high resolution typing) or a haploidentical related donor; unrelated donors are identified through the National Marrow Donor Program.
Design

For Recipients with Matched Donors

  • Patients with PID receiving a high intensity transplant conditioning regimen will receive a regimen consisting of fludarabine 40 mg/m(2) IV once daily for 4 days on days -6, -5, -4, and -3, busulfan IV once daily for 4 days on days -6, -5, -4, -3 (busulfan dose will be based on pharmacokinetic levels from the test dose and will be targeted to an AUC of 3200-4400 microMol X min/L (52-65 mg X h/L) (3.2 mg/kg IV per day will be the default dose), and HSCT on day 0.
  • Patients with PID receiving an intermediate intensity transplant conditioning regimen will receive a regimen consisting of of fludarabine 40 mg/m(2) IV once daily for 4 days on days -6, -5, -4, and -3, busulfan IV once daily for 3 days on days -6, -5, -and -4 (busulfan dose will be based on pharmacokinetic levels from the test dose and will be targeted to an AUC of 3200-4400 microMol X min/L (52-65 mg X h/L) (3.2 mg/kg IV per day will be the default dose), and HSCT on day 0.
  • Patients with PID receiving a low intensity transplant conditioning regimen will receive a regimen consisting of fludarabine 40 mg/m2 IV once daily for 4 days on days -6, -5, -4, and -3, busulfan IV once daily for 2 days on days -6, and -5 (busulfan dose will be based on pharmacokinetic levels from the test dose and will be targeted to an AUC of 3200-4400 microMol X min/L (52-65 mg X h/L) (3.2 mg/kg IV per day will be the default dose), and HSCT on day 0.

In all cohorts, patients with clinical evidence of immune dysregulation, alemtuzumab will be given at the dose of 0.03 mg on day -11, 0.1 mg/kg on day -10, and 0.2 mg/kg on days -9 and -8.

For Recipients with 9/10 or 8/10 Matched Donors and Haploidentical Related Donors

  • Patients with PID receiving a high intensity transplant conditioning regimen will receive a regimen consisting of fludarabine 40 mg/m2 IV once daily for 4 days on days -6, -5, -4, and -3, busulfan IV once daily for 3 days on days -6, -5, and -4 (busulfan dose will be based on pharmacokinetic levels from the test dose and will be targeted to an AUC of 3200-4400 microMol X min/L (52-65 mg X h/L) (3.2 mg/kg IV per day will be the default dose), 200 cGy TBI on day -1, and HSCT on day 0.
  • Patients with PID receiving an intermediate intensity transplant conditioning regimen will receive a regimen consisting of fludarabine 40 mg/m2 IV once daily for 4 days on days -6, -5, -4, -and 3, busulfan IV once daily for 2 days on days -6, -and -5 (busulfan dose will be based on pharmacokinetic levels from the test dose and will be targeted to an AUC of 3200-4400 microMol X min/L (52-65 mg X h/L) (3.2 mg/kg IV per day will be the default dose), 200 cGy TBI on day -1, and HSCT on day 0.
  • Patients with PID receiving a low intensity transplant conditioning regimen will receive a regimen consisting of fludarabine 40 mg/m(2) IV once daily for 4 days on days -6, -5, -4, and -3, busulfan IV once daily for 1 day on day -6 (busulfan dose will be based on pharmacokinetic levels from the test dose and will be targeted to an AUC of 3200-4400 microMol X min/L (52-65 mg X h/L) (3.2 mg/kg IV per day will be the default dose), 200 cGy TBI on day -1, and HSCT on day 0.

In all cohorts, patients with clinical evidence of immune dysregulation, alemtuzumab will be given at the dose of 0.03 mg/kg on day -11, 0.1 mg/kg on day -10, and 0.2 mg/kg on days -9 and -8.

For Post-Transplant GVHD Prophylaxis

-Post-transplant GVHD prophylaxis in all groups will consist of cyclophosphamide 50 mg/kg IV once daily for 2 days on days +3 and +4, along with mycophenolate mofetil from day +5 to approximately day +35 and tacrolimus from day +5 to approximately day +180. If there is no evidence of GVHD, tacrolimus will be stopped or tapered at approximately day +180.

Details
Condition Immunodeficiency, Disorder of immune system, Lymphoproliferative Disorder, Common Variable Immunodeficiency, Common Variable Immunodeficiency (CVID), Autoimmune Lymphoproliferative, Primary Immunodeficiency Disorders, Lymphoproliferative disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, lymphoproliferative disease, immune disorder, immune disorders, immunologic disease, immune dysfunction, immune disease, immun, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders, Primary T-cell Immunodeficiency Disorders
Treatment busulfan, Fludarabine, Total body irradiation, alemtuzumab, Mycophenolate Mofetil (MMF), allogeneic HSCT, Busulfan Test dose, Tacrolimus (Tacro), Cyclophosphamide (Cytoxan)
Clinical Study IdentifierNCT04339777
SponsorNational Cancer Institute (NCI)
Last Modified on12 September 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Age >= 4 years and <= 69 yo with Weight >=12 kilograms
Mutation in a known monogenic Primary Immunodeficiency Disease (PID) gene or Primary Immune Regulatory Disorder (PIRD) performed by a CLIA certified laboratory, who have failed standard medical management, or when no standard medical management is available. OR
Patients without a known PID or PIRD mutation may be eligible if they have a clinical history that is characteristic of an individual with an immune defect including a history of infections requiring prolonged courses of therapy or evidence of immune dysregulation manifested by autoimmune/autoinflammatory disease, atopy, hemophagocytic lymphohistiocytosis, hypogammaglobulinemia, or impaired response to vaccination. A virally-driven malignancy alone will also constitute basis for inclusion
Availability of a 10/10 or 9/10 or 8/10 HLA-matched related or unrelated donor (if the mismatch is at DQ this will be considered an 8/8 matched donor), or a haploidentical related donor
Karnofsky or Lansky performance status of >= 40%
Creatinine: Adult patients: <= 2.0 mg/dl and creatinine clearance >=30 ml/min; Pediatric patients (<18 years old): creatinine < 1.5 mg/dL and a creatinine clearance, using the Schwartz Formula > 30 mL/min/1.73m^2
Adequate end-organ function, as measured by
Serum conjugated bilirubin < 2.5 mg/dl; serum ALT and AST 5 times upper limit of normal
Pulmonary function tests: FEV1 > 30% and DLCO >30%. Children who are unable to have DLCO assessed due to age, are still eligible if no evidence of dyspnea at rest and no need for supplemental oxygen
Left ventricular ejection fraction > 40%, preferably by 2-D echocardiogram (ECHO) obtained within 60 days prior to enrollment
Ability of subject or parent/guardian to understand and the willingness to sign a written informed consent document. For subjects <18 years old, their legal guardian must give informed consent. Pediatric patients will provide assent
As therapeutic agents used in this trial may be harmful to a fetus, women of childbearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for at least one-year post-allo HCT. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in the study, she should inform her treating physician immediately
Willingness to remain in the NIH hospital or, if discharged, stay close to the NIH, for a minimum of 100 days after transplant or longer, if there are complications. If outpatient in the first 100 days after transplant, patient must commit to having an adult caregiver with them at all times

Exclusion Criteria

Patients who are receiving any other investigational agents with the exception of virus-specific cytotoxic T-cells for the treatment of viral infection/reactivation prior to allo HCT
Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events
HIV-positive patients are ineligible because these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents (steroids, cyclophosphamide, busulfan, sirolimus, MMF, G-CSF) used in the study
Active psychiatric disorder which is deemed by the PI to have significant risk of compromising compliance with the transplant protocol or which does not allow for appropriate informed consent
Pregnant women are excluded from this study because the study agents have the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with the study agents, breastfeeding should be discontinued if the mother is treated with the study agents
Uncontrolled intercurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
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